Total Syntheses of Morphine

The earlier work on the the synthesis of opium alkaloids has been summarised (ref. 168) but the strategies in two can be briefly summarised. In the first synthesis of morphine (ref. 169) an early stage consisted of a Diels-Alder reactionof5,6-dimethoxy-4-cyanomethylnaphtho-1,2-quinoneandbuta-1,3-diene to form the phenanthrene shown, a reaction which had been used 

Both the preceding syntheses were multi-step procedures with a classical approach and subsequent work turned towards strategies modelled on biogenetic lines via for example the oxidative coupling of a phenolic 

With the related 6-methoxy compound shown the cyclisation to a morphinan with hydrochloric acid proceeded to the unwanted product C in 37% yield and the desired one in only a 3% yield (ref. 179). The same precursor, synthesised from 2-(3-methoxyphenyl)ethylamine and 3,4-dimethoxyphenylacetic acid by amide formation and ring closure by the Bischler-Napieralski cyclisation, followed by reduction, methylation and Birch reduction, was used by others with similar results (ref. 180). The route constitutes a synthesis of morphine by the use of the final steps of earlier work (refe. 169,171), albeit in low yield, although in considerably fewer steps than the earlier syntheses. 

HCOjEt, (v)80% H2SO4 lEtp, (vi) 5-chlorotetrazole, (vii)Pd-C,base,(viii)HCI/MeOH CHjO, Pt-C.Hj 

DeGraw (ref.184) and explains their failure]. Hydrolysis of the formyl group, bromination, alkaline treatment to effect oxide ring formation and finally hydrogenation in the presence aqueous formaldehyde afforded racemic dihydrocodeinone. 

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Another 6-exo closure from our enantioselective total syntheses of (— )-morphine (40) and its enantiomer was published in 1993 (Scheme 6-7) [12]. The pivotal cyclization of 38 to 39 was accomplished in 60% yield. This is a demanding intramolecular Heck reaction, since the palladium-bond arylmethyl side chain of 38 must rotate over the octahydroisoquinoline ring to coordinate with the trisubstituted alkene. Reflecting this difficulty, Pd(OCOCF3)2(PPh3)2 [a precatalyst that generates the reactive Pd(0) catalyst Pd(PPh3)2] and a cyclization temperature of 120°C were required. 

Despite a series of newer enantioselective total syntheses of morphine and thebaine, these compounds will continue to be isolated from renewable raw materials and then converted by chemical methods into the corresponding drug substances. 

Kametani, T. lhara, M. Fukumoto, K. Yagi, H. Studies on the Syntheses of Heterocyclic Compounds. Part CCC. Syntheses of Salutaridine, Sinoacutine, and Thebaine, Formal Total Syntheses of Morphine and Simomenine J. Chem. Soc. (C) 1969, 2030-2033. 

In the synthesis of morphine, bis-cyclization of the octahydroisoqtiinolinc precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the rr-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (-)- and (+ )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

The -elimination of a thiyl radical (RS ) terminated a remarkably productive tandem radical bicyclization in Parker s formal total syntheses of ( )-codeine and ( )-morphine (see Scheme 14).29 Subjection of aryl bromide 72 to the conditions indicated generates transient aryl radical 73, an intermediate which engages the substi-... 

The structure of morphine was first determined in 1925 by Sir Robert Robinson (1886— 1975) and John Masson Gulland (1898-1947). A total synthesis of morphine was achieved in 1952 at the University of Rochester by Marshall D. Gates (1915—2003) and his co-worker Gilg Tschudi. Since its first synthesis, a number of other processes have been used to synthesize morphine in the laboratory, but none of these is economically viable. Therefore morphine continues to be obtained through biosynthesis from poppy plants. 

In the total synthesis of (-)-morphine, the pivotal tetracyclic intermediate was generated as depicted below. Thus, this core structure was synthesized by reduction of the enone to afford an allylic alcohol, which was then briefly exposed to BBr, to give the desired skeleton in 64% yield <02JA12416>. 

The elegant formal total synthesis of morphine, accomplished by Parker, shows some similarities to that of Fuchs through analogous disconnections. In both syntheses, the core of the molecule was formed as a result of a tandem process in this case as a result of a radical cascade.79 80 The immediate cyclization precursor 191 was prepared via a Mitsunobu reaction between monoprotected cw-diol 189 (prepared in 8 steps from 2-((3-methoxyphenyl)ethylamine) in 47% overall yield) and phenol 188, followed by cleavage of the silyl ether, Scheme 21. The key step, homolytic cleavage of the Ci2-Br... 

New aromatic annulation methods total syntheses of juncusol, sendaverine, and morphine -related analgesics... 

Abstract This review summarizes recent developments in the total synthesis of morphine alkaloids and some of the semisynthetic derivatives. The literature is covered for the period of 5 years after the pubhcation of the last review in 2005. The syntheses that appeared in this period are covered in detail and are placed in the context of all syntheses of opiate alkaloids since the original one pubhshed by Gates in 1952. The introduction covers the historical aspects of total synthesis of these alkaloids. The synthesis of some of the medicinally useful derivatives is reviewed in the last section along with some of the methodology required for then-preparation. 

The chemistry of natural products encompasses their isolation, structure elucidation, partial and total synthesis, elucidation of their biogenesis, and the biomi-metic synthesis of N. p. Major breakthroughs in analysis were, e.g., the structural clarifications of morphine, lignin, insulin, estrones, and cholesterol as well as the elucidation of the biosyntheses of terpenoids, morphine, penicillin, chlorophyll, and vitamin B 2. Major advances in synthetic chemistry were, e.g., the total syntheses of camphor, hemin, quinine, saccharose, tropine, stryehnine, chlorophyll, vitamin B 2, erythromycin, taxol and palytoxin. Numerous N. p. of the so-ealled ehiral pool are used as starting materials for the synthesis of optically active compounds or serve (in the form of their derivatives) as catalysts for enantioselective syntheses. 

In 1952, Marshall D. Gates and Gilg Tschudi reported the first total synthesis of morphine. [93, 94] Since then, about 20 syntheses of racemic morphine have been published. [95] Only in 1993, Larry E. Overman could obtain (-)-mor-phine by an enantioselective synthesis. [96] Further syntheses followed in 1996 by Johann Mulzer [97], in 1997 by James White [98], in 2002 by Douglas Taber [99] andBarryTrost [100], and bymany others [101] as well (Tab. 5.6). Measured by the number of stages and the overall yield, the total syntheses by Rice in 1980 and Trost in 2002 are particularly noteworthy. 

Other examples of alkaloids possessing the morphinan skeleton include sinomenine [6—8] isolated from the roots of Sinomenium acutum (Menisper-maceae), and metaphanine [9—14] isolated from the stems of Stephania japonica (Menispermaceae). Sinomenine possesses the mirror image skeleton to that of morphine, and is derived from (S)-reticuline. On the other hand, metaphanine possesses the hasubanan skeleton. Total syntheses of metaphanine have been reported [15,16]. 

Both Parsons [49] and Mulzer [50, 51] used related Eschenmoser-Claisen rearrangements to set a benzylic quaternary stereocenter in their approach to morphine alkaloids (Scheme 7.25) [5, 52, 53]. Reduction of cyclohexenone 65 followed by Eschenmoser-Claisen rearrangement gave unsaturated amide 66, which was subsequently converted into a known precursor of morphine (Scheme 7.24, Eq. 1). Treatment of the acid sensitive phenanthrenol 67 with dimethylacetamide dimethyl acetal (4) afforded amide 68 comprising the entire carbon skeleton of the morphine (Eq. 2). The amide was subsequently reduced to a primary alcohol (69) using lithium triethylborohydride (Super-Hydride), the most suited reagent to perform this task. Previous total syntheses of the alkaloid were intercepted at the stage of dehydrocodeinone. 

Even more than 60 years after the first total synthesis of morphine by Gates [139, 140], the ongoing interest of synthetic chemists in the natural product is evidenced by the numerous approaches to the morphinan skeleton, as well as formal and total syntheses of the natural product. The progress in morphine synthesis has been reviewed on several occasions [141-143]. 

Morphine (10) and codeine (11), constituents of opium, are the most interesting alkaloids found in nature. Morphine is also the oldest alkaloid isolated, in 1805, by the German pharmacist Sertiimer from opium, the sun dried latex of Papaver somniferum. The structure of morphine with its so-called morphinan skeleton, once called the acrobat under the alkaloids, was finally elucidated in 1952 by the first total synthesis performed by Gates and Tschudi. Many syntheses would follow [26], but all morphine used today, whether legal or illicit, originates in the natural source P. somniferum or its extract, opium. The latex may contain up to 20% morphine. Most legal morphine is converted into the anticough medicine codeine (Table 5.1) by treatment with trimethylanilinium methoxide, whereas almost all illicit morphine is acetylated to the diacetate heroin. 

The most known narcotics are the opium alkaloids such as morphine, codeine, thebaine, papaverine, noscapine and their derivatives and modified compounds such as nalmorphine, apomorphine, apomopholcodine, dihydrocodeine, hydro-morphone and heroine, also known as diamorphine. Synthetic narcotics share the structural skeleton of morphine and include dextromethorphan, pentazocine, phenazocine meperidine (pethidine), phentanyl, anfentaitil, remifentalin, methadone, dextropropoxyphene, levoproxyphene, dipipanone, dextromoramide, meptazinol and tramadol. Thebaine derivatives are also modified narcotics and include oxycodone, oxymorphone, etorphine, buprenorphine, nalbuphine, naloxone or naltrexone. Narcotics can be semi-synthesized or totally synthesized from the morphine and thebaine model. The compounds serve various purposes in clinical practise. 

A total of more than 20 total syntheses have been described which aim to generate the most important members of the morphinan-type alkaloids, morphine and codeine. These long-standing efforts in alkaloid synthesis have been primarily due to the exceptional pharmacological importance of both compounds, as the most efficacious therapies for pain and cough, respectively. 

Intramolecular Heck reactions for building up complex oxacyclic skeletons are a common theme in the synthesis of natural products. These reactions are exceptionally valuable for the installation of quaternary carbon stereocenters. In the morphine total syntheses by Overman <1994PAC1423> and Trost et al., intramolecular Heck reactions to form dihydrobenzofurans served as strategic key steps (Equation 138) <2005JA14785>. Asymmetric variants of intramolecular Heck reactions based on BINAP ligands to yield dihydrobenzofurans have also been investigated <1998T4579>. 

A later report of the total synthesis of ( -methylpallidinine (106) involved construction of the morphinan nucleus by addition of diazomethane to an iminium salt. The requisite iminium salt 104 was synthesized from the ketone 103 as shown in Scheme 20. When the iminium salt 104 was treated with diazomethane, the morphinan 105 was directly formed in 30% yield along with the aziridinium ion. In Evans s morphine synthesis, a morphinan product was produced directly in 30% yield from reaction of diazomethane... 

In this chapter, a brief overview of the state of the art of morphine research is provided along with a detailed review of the several total syntheses that have materialized to date. Some approaches to the general skeleton of morphine alkaloids are also presented in order that such attempts may be put in perspective with the completed studies. Omitted from the review are the syntheses of derivatives and pharmaceuticals resulting from manipulation of the natural product itself. The authors would hope that the comparison of total synthetic approaches will serve to inspire the creative reader and lead to an efficient and artistic attainment of the title compound in the future. The literature in this area has been reviewed through the end of 1994. 

In fact, the most probable structure of morphine was put forward in the year 1925 however, its confirmation by total synthesis was aeeomplished in 1955. Interestingly, the paueity of the knowledge with regard to the correct structure of morphine, nevertheless subsided the zeal and enthusiasm amongst the medicinal chemists to synthesize several morphine struetural analogues by taking advantage of the various known chemical reactions with the peripheral funetional moieties present in morphine, such as ... 

Moos WH, Gless RD, Rapoport H (1983) Codeine analogs - synthesis of 4a-aryldecahy-droisoquinolines containing nitrogen ring functionality and of octahydro-1 h-indeno[l,2,3-ef]isoquinolines - a total synthesis of codeine. J Org Chem 48 227-238 Toth JE, Euchs PL (1987) Syntheses via vinyl sulfones. 21. Total synthesis of dl-morphine. 

Substructure type A (Figure 6.3) has also been employed in total synthesis of some O-heterocyclic-containing natural products. Key intermediates 47 and 49 in the syntheses of (-)-galanthamine [61,62] and morphine or noroxymorphone [62,63] have been prepared by means of an intramolecular Mizoroki-Heck reaction (Scheme 6.16). 

The literature of organic chemistry is replete with attempts to synthesize morphine and codeine and a number of successes have been achieved. The first total synthesis of codeine and morphine, completed in 1952 (that of Gates and Tschudi ), is shown in Scheme 13.44. 

Heroin (Figure 16.1a) is the most widely abused semisynthetic opiate. It was first synthesized in 1874 by acetylation of morphine (Figure 16.1b). Heroin is usually seen as a white crystalline powder and is mixed with diluents in illicit samples, such as sugar, quinine, caffeine, and even strychnine. Therefore it is necessary for chromatographic systems to resolve heroin and its commonly encountered diluents. In street samples heroin may comprise as low as 2% by weight of the total sample, which causes difficulty with separation when it is... 

Meperidine hydrochloride (the full name) is a synthetic opioid. It is synthesized by the reaction of chemicals not found in opium. Specifically, meperidine hydrochloride is produced by the reaction of dichlorodi-ethyl methylamine with benzyl cyanide, to produce ethyl l-methyl-4-phenyl-isonipecotate hydrochloride (meperidine s chemical name). Some references to meperidine classify it as a totally synthetic opioid. Semi-synthetic opioids are produced by using one of the opiates as a starting material. Two examples of semi-synthetic opioids are hydrocodone and heroin. Hydrocodone is produced by the chemical modification of codeine, while heroin is made by chemically altering morphine. 

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